According to a recent report from the Centers for Disease Control, the number of obese adults in the United States has doubled in the past 20 years and nearly 2/3 of the adult population is now overweight or obese. Given that obesity is a risk factor for numerous other diseases including cancer, cardiovascular disease and diabetes, the public health implications of these statistics are staggering. This ongoing epidemic results from an interaction between physiology and an increasingly obesigenic environment, including ubiquitous access to low-cost high-fat foods. PPARg is a transcription factor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic responses in liver, muscle and white adipose tissue. Although PPARg is also expressed in the hypothalamus, and although the hypothalamus plays an important role in the central regulation of glucose and lipid homeostasis, virtually nothing is known about the function of hypothalamic PPARg. This proposal will test the overall hypothesis that central PPARg modulates energy balance and that this may be an important mechanism by which consumption of dietary fats contributes to obesity. We plan to test the overall hypothesis by pursuing three specific aims. Specific Aim 1: To test the hypothesis that activation of central PPARg by its physiological and pharmaceutical agonists facilitates positive energy balance. Specific Aim 2: To test the hypothesis that CMS PPARg activation facilitates positive energy balance by reducing MC4 receptor activation. Specific Aim 3: To test the hypothesis that activation of CMS PPARg is a key part of high-fat diet-induced leptin resistance and obesity. Tests of these hypotheses will require experiments using acute pharmacological inhibition or activation of CNS PPARg in various dietary models and in MC4 knockout mice, complemented by experiments using chronic reduction in PPARg expression by injection of a short-hairpin RNA with a lentivirus vector into the arcuate nucleus of the hypothalamus. PUBLIC HEALTH RELEVANCE: The expected contribution of the proposed studies is to describe a pathway which directly links dietary fat to overeating and increased body fat. This contribution is significant because it is expected to provide the knowledge needed to 1) develop pharmacological interventions to modulate this pathway and/or 2) develop appropriate dietary guidelines to relieve the growing public health burden of obesity and obesity- related diseases. Given the wide use of PPARg agonists to treat type II diabetes, this work also has the potential to shed considerable light on underlying mechanisms of the weight gain caused by these drugs.